Abstract
Background. Recombinant tissue plasminogen activator (rtPA) is the only recommended pharmacological treatment for acute ischemic stroke, but it has a restricted therapeutic time window. When administered at time points greater than 4.5 h after stroke onset, rtPA disrupts the blood-brain barrier (BBB), which leads to serious brain edema and hemorrhagic transformation. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; however, researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. Objective. The present study was conducted to test the hypothesis that EA extends the therapeutic time window of rtPA for ischemic stroke in a male rat model of embolic stroke. Methods. SD rats were randomly divided into the sham operation group, model group, rtPA group, EA+rtPA group, and rtPA+MEK1/2 inhibitor group. An injection of rtPA was administered 6 h after ischemia. Rats were treated with EA at the Shuigou (GV26) and Neiguan (PC6) acupoints at 2 h after ischemia. Neurological function, infarct volume, BBB permeability, brain edema, and hemorrhagic transformation were assessed at 24 h after ischemia. Western blotting and immunofluorescence staining were performed to detect the levels of proteins involved in the ERK1/2 signaling pathway (MEK1/2 and ERK1/2), tight junction proteins (Claudin5 and ZO-1), and MMP9 in the ischemic penumbra at 24 h after stroke. Results. Delayed rtPA treatment aggravated hemorrhagic transformation and brain edema. However, treatment with EA plus rtPA significantly improved neurological function and reduced the infarct volume, hemorrhagic transformation, brain edema, and EB leakage in rats compared with rtPA alone. EA increased the levels of tight junction proteins, inhibited the activation of the ERK1/2 signaling pathway, and reduced MMP9 overexpression induced by delayed rtPA thrombolysis. Conclusions. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB.
Highlights
Stroke is a leading cause of mortality and disability worldwide [1]; approximately 13.7 million new stroke cases, 5.5 million deaths, and 116.4 million disability-adjusted lifeyears due to stroke were reported in 2016 [2]
We evaluated neurological deficits and the cerebral infarct volume at 24 hours after stroke to determine the effects of EA on delayed Recombinant tissue plasminogen activator (rtPA) thrombolysis for ischemic stroke
The combination of EA and 6 h rtPA resulted in significant reductions in the neurological deficit score and infarct volume compared to the model group and to the group treated with 6 h rtPA alone (p < 0:05, p < 0:01, Figures 1(a) and 1(c))
Summary
Stroke is a leading cause of mortality and disability worldwide [1]; approximately 13.7 million new stroke cases, 5.5 million deaths, and 116.4 million disability-adjusted lifeyears due to stroke were reported in 2016 [2]. The use of rtPA is restricted by its narrow thrombolytic time window, because it may cause thrombolytic complications, such as brain edema and hemorrhagic transformation, when delayed thrombolysis is initiated after 4.5 h [6, 7]. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB
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